The HLA-I landscape confers prognosis and antitumor immunity in breast cancer.

Breast cancer is a highly heterogeneous disease with varied subtypes, prognoses and therapeutic responsiveness. Human leukocyte antigen class I (HLA-I) shapes the immunity and thereby influences the outcome of breast cancer. However, the implications of HLA-I variations in breast cancer remain poorly understood. In this study, we established a multiomics cohort of 1156 Chinese breast cancer patients for HLA-I investigation. We calculated four important HLA-I indicators in each individual, including HLA-I expression level, somatic HLA-I loss of heterozygosity (LOH), HLA-I evolutionary divergence (HED) and peptide-binding promiscuity (Pr). Then, we evaluated their distribution and prognostic significance in breast cancer subtypes. We found that the four breast cancer subtypes had distinct features of HLA-I indicators. Increased expression of HLA-I and LOH were enriched in triple-negative breast cancer (TNBC), while Pr was relatively higher in hot tumors within TNBCs. In particular, a higher Pr indicated a better prognosis in TNBCs by regulating the infiltration of immune cells and the expression of immune molecules. Using the matched genomic and transcriptomic data, we found that mismatch repair deficiency-related mutational signature and pathways were enriched in low-Pr TNBCs, suggesting that targeting mismatch repair deficiency for synthetic lethality might be promising therapy for these patients. In conclusion, we presented an overview of HLA-I indicators in breast cancer and provided hints for precision treatment for low-Pr TNBCs.

Guanosine diphosphate-mannose suppresses homologous recombination repair and potentiates antitumor immunity in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis. TNBCs with high homologous recombination deficiency (HRD) scores benefit from DNA-damaging agents, including platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, whereas those with low HRD scores still lack therapeutic options. Therefore, we sought to exploit metabolic alterations to induce HRD and sensitize DNA-damaging agents in TNBCs with low HRD scores. We systematically analyzed TNBC metabolomics and identified a metabolite, guanosine diphosphate (GDP)-mannose (GDP-M), that impeded homologous recombination repair (HRR). Mechanistically, the low expression of the upstream enzyme GDP-mannose-pyrophosphorylase-A (GMPPA) led to the endogenous up-regulation of GDP-M in TNBC. The accumulation of GDP-M in tumor cells further reduced the interaction between breast cancer susceptibility gene 2 (BRCA2) and ubiquitin-specific peptidase 21 (USP21), which promoted the ubiquitin-mediated degradation of BRCA2 to inhibit HRR. Therapeutically, we illustrated that the supplementation of GDP-M sensitized DNA-damaging agents to impair tumor growth in both in vitro (cancer cell line and patient-derived organoid) and in vivo (xenograft in immunodeficient mouse) models. Moreover, the combination of GDP-M with DNA-damaging agents activated STING-dependent antitumor immunity in immunocompetent syngeneic mouse models. Therefore, GDP-M supplementation combined with PARP inhibition augmented the efficacy of anti-PD-1 antibodies. Together, these findings suggest that GDP-M is a crucial HRD-related metabolite and propose a promising therapeutic strategy for TNBCs with low HRD scores using the combination of GDP-M, PARP inhibitors, and anti-PD-1 immunotherapy.

Genomic alterations affecting tumor-infiltrating lymphocytes and PD-L1 expression patterns in triple-negative breast cancer.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) and programmed cell death 1 ligand 1 (PD-L1) remain imperfect in predicting clinical outcomes of triple-negative breast cancer because outcomes do not always correlate with the expression of these biomarkers. Genomic and transcriptomic alterations that may contribute to the expression of these biomarkers remain incompletely uncovered. METHODS: We evaluated PD-L1 immunohistochemistry scores (SP142 and 28-8 assays) and TILs in our triple-negative breast cancer multiomics dataset and 2 immunotherapy clinical trial cohorts. Then, we analyzed genomic and transcriptomic alterations correlated with TILs, PD-L1 expression, and patient outcomes. RESULTS: Despite TILs serving as a decent predictor for triple-negative breast cancer clinical outcomes, exceptions remained. Our study revealed that several genomic alterations were correlated with unexpected events. In particular, PD-L1 expression may cause a paradoxical relationship between TILs and prognosis in certain patients. Consequently, we classified triple-negative breast cancers into 4 groups based on PD-L1 and TIL levels. The TIL-negative PD-L1-positive and TIL-positive PD-L1-negative groups were not typical "hot" tumors; both were associated with worse prognoses and lower immunotherapy efficacy than TIL-positive PD-L1-positive tumors. Copy number variation of PD-L1 and oncogenic signaling activation were correlated with PD-L1 expression in the TIL-negative PD-L1-positive group, whereas GSK3B-induced degradation may cause undetectable PD-L1 expression in the TIL-positive PD-L1-negative group. These factors have the potential to affect the predictive function of both PD-L1 and TILs. CONCLUSIONS: Several genomic and transcriptomic alterations may cause paradoxical effects among TILs, PD-L1 expression, and prognosis in triple-negative breast cancer. Investigating and targeting these factors will advance precision immunotherapy for patients with this disease.

Bidirectional crosstalk between therapeutic cancer vaccines and the tumor microenvironment: Beyond tumor antigens.

Immunotherapy has rejuvenated cancer therapy, especially after anti-PD-(L)1 came onto the scene. Among the many therapeutic options, therapeutic cancer vaccines are one of the most essential players. Although great progress has been made in research on tumor antigen vaccines, few phase III trials have shown clinical benefits. One of the reasons lies in obstruction from the tumor microenvironment (TME). Meanwhile, the therapeutic cancer vaccine reshapes the TME in an ambivalent way, leading to immune stimulation or immune escape. In this review, we summarize recent progress on the interaction between therapeutic cancer vaccines and the TME. With respect to vaccine resistance, innate immunosuppressive TME components and acquired resistance caused by vaccination are both involved. Understanding the underlying mechanism of this crosstalk provides insight into the treatment of cancer by directly targeting the TME or synergizing with other therapeutics.

[Use of fiber-reinforced chemical curing resin to close the inter-proximate space of the posterior teeth].

PURPOSE: To investigate the clinical efficacy of using fiber-reinforced chemical curing resin to close the inter-proximate space of the posterior teeth and block the food impaction. METHODS: One hundred and sixty-two patients with food impaction of posterior teeth were selected in this study. The total number of the food impaction was 170. They were divided into narrow-gap group and wide-gap group according to the damage of the inter-proximate space. Jingjin enamel adhesive reinforced polyethylene fiber ribbon was used in both group to close the inter-proximate space. The patients were reviewed at 6-month and 1-year. After the second follow-up examination, 161 restorations of 154 patients were included in this study. The differences between the 2 groups were analyzed by Chi-square test with SPSS 13.0 software package. RESULTS: Statistical differences were found in the retention rate of the restorations at 6-month between the 2 groups (P<0.05). The retention rate in the narrow-gap group was significantly lower than that in the wide-gap group. However, there was no significant difference between the 2 groups at 1-year. There was no significant difference in integrality between the 2 groups at 6-month and 1-year. CONCLUSIONS: The use of fiber-rein forced chemical curing resin to close the inter-proximate space of the posterior teeth and block the food impaction is more suitable for patients with clinical crown elongation, gingival recession, alveolar bone loss and the tissue damages in the inter-proximate space, which will cause food impaction.

Expression and significance of VEGF and p53 in degenerate intervertebral disc tissue.

OBJECTIVE: To investigate the mechanism of expression and significance of vascular endothelial growth factor (VEGF) and p53 in degenerate intervertebral disc tissue. METHODS: Pathological sections collected from 156 patients with lumbar disc herniation after surgery were tested by immunohistochemistry method, for evaluation of the expression of VEGF and p53 in degenerate intervertebral disc tissue. RESULTS: 98 cases (62.8%) with vascular infiltration phenomenon are found, and positive rates of VEGF and p53 in degenerate intervertebral disc tissue are 73.42% (116/156) and 58.97% (92/156); co-expression rate is 53.2%(83/156); the expression rates of VEFG and p53 are significantly higher in the tissue with blood vessel infiltration than in the tissue without infiltration; there is a close relationship of VEGF with p53. CONCLUSIONS: VEGF and p53 gene synergetic express in degenerate intervertebral disc tissue, working together in neovascularization and infiltration, and accelerating intervertebral disc tissue degeneration.

[Therapeutic effect of electroacupuncture on chronic orchialgia].

OBJECTIVE: To compare the efficiency difference in chronic orchialgia between electroacupuncture and western medicine and explore the better therapy for chronic orchialgia. METHODS: Eighty-six cases of chronic orchialgia were randomly divided into an electroacupuncture group (56 cases) and an Indomethacin group (30 cases). Except the conventional oral administration of Amitriptyline for anti-depression, electroacupuncture was applied at Shenshu (BL 23), Ciliao (BL 32), Sanyinjiao (SP 6), Taichong (LR 3) and others in electroacupuncture group, and Indometacin suppository anal therapy was used in Indometacin group. The session of treatment in two groups was 2 weeks. Before and after treatment, pain number assessment scale was adopted for the assessment of pain severity separately to compare the differences in pain score on 3rd, 7th, 10th and 14th days after treatment. RESULTS: The pain score at each time point was improved remarkably as compared with that before treatment in two groups (P < 0.05, P < 0.01). In comparison on the 7th, 10th and 14th days of two groups, the pain scores in electroacupuncture group was lower than those in Indometacin group (all P < 0.05). CONCLUSION: Electroacupuncture combined with Amitriptyline treatment is quite effective on chronic orchialgia, which is superior to the effect of Indo methacin combined with Amitriptyline treatment and deserves to be promoted in application.

[Clinical observation of 45 cases with radicular cyst treated with non-surgical methods].

PURPOSE: To observe the clinical effect and the influential factors of non-surgical treatment of radicular cyst. METHODS: A total of 45 cases with radicular cyst were included from 2002 to 2008. They were treated by non-surgical treatment including decompression of cyst cavity or overfilling of the root canal. All the patients were examined at 3,6 months and 1,2,3 years after treatment. The therapeutic result was analyzed with SPSS15.0 software package for X(2) test. RESULTS: Of the 45 cases, 22 were cured at a follow-up period of 1-4 years, the cure rate was 48.89%. Seventeen cases were improved, the improvement rate 37.78%, and the total efficiency rate was 86.67%. Six cases failed to the treatment, and the failure rate was 13.33%. CONCLUSIONS: With decompression of cyst cavities or overfilling of the root canals, non-surgical treatment of radicular cyst is a simple, economical, safe, and effective treatment modality.

[Evaluation of the clinical effect of the teeth with subgingivally involved defect conserved by crown lengthening surgery].

PURPOSE: To evaluate the clinical effect of the teeth with subgingivally involved defect which were conserved by crown lengthening surgery. METHODS: 62 teeth, with defect subgingivally from 1.5 mm to 4 mm, mobility degree(MD)0.05), but a significant increase about MD occurred in the major defect group one year after restoration (P<0.01), and there was significant correlation between MD of each stage after operation and PD of pre-operation in anterior teeth (r=0.489, 0.526, 0.531, P<0.01). CONCLUSIONS: According to the biological width principle, crown lengthening surgery may conserve these teeth with subgingivally involved defect, and has a good, long-time clinical effect. But MD showed an increasing trend after operation and significant cor.

[Experience of repairing alveolar bone defects by collagen membrane and hydroxyapatite and its long-term result].

PURPOSE: To observe the clinical effect of using the domestic BME-10X medical collagen membrane and hydroxyapatite (HA) in guide tissue regeneration of the bone defects caused by periodontitis and periapical cyst. METHODS: 18 cases with 9 points in 9 teeth with II degree furation involvement, 16 points in 11 teeth with 2 or 3 bone bottom pockets and 6 cases with periapical cyst were chosen in our study. The defect region of alveolar bone was stuffed with HA and covered with collagen membrane. The pathological changes after over one year were observed and recorded. RESULTS: The pathological changes of alveolar bone defects were significant in 7 cases with furcation involvements (77.8%),12 cases with bone bottom pockets (75%),and 6 cases of periapical cyst (100%). CONCLUSION: The combination of collagen membrane and HA can be applied in repairing the alveolar bone defects resulting form periodontitis and periapical cysts.